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Promising HIV Vaccine Strategies: Where

We Have BeenWhere We Are Going

Barton Haynes

September 11, 2011

Bangkok, Thailand

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HIV Vaccine Development

Virus discovered 1983

Cause of AIDS 1984

Vaccine development began1984

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HIV Vaccine Development

Hepatitis B virus vaccine is theouter coat (envelope)

1984- take the outer coat of HIV

gp120 (envelope) and make thevaccine

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HIV Vaccine Development

Protection from virusesantibodies that block(neutralize) virus

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HIV Vaccine Development

HIV mutatesdiverse

--strains we used in thelaboratory not like strains infield

--Lab cultured strains easy toneutralize while field strains

difficult 6

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HIV Vaccine Development

Vaccines induce antibodiesagainst regions of the envelopethat neutralize the easy toneutralize HIV strains but do notneutralize field HIV strains.

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Membrane proximal

Carbohydrate

CD4 binding site

V3 Loop

V1V2 Loops

V2,V3 Quaternary

(conformational)

CD4 binding site

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Membrane proximal

Carbohydrate

CD4 binding site

V3 Loop

V1V2 Loops

V2,V3 Quaternary

(conformational)

CD4 binding site

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Membrane proximal

Carbohydrate

CD4 binding site

V3 Loop

V1V2 Loops

V2,V3 Quaternary

(conformational)

CD4 binding site

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Membrane proximal

Carbohydrate

CD4 binding site

V3 Loop

V1V2 Loops

V2,V3 Quaternary

(conformational)

CD4 binding site

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HIV Vaccine Development

AIDSVAX B/B 2 clade B

envelopes (Westernhemisphere)trial did notprotect

AIDSVAX B/E 1 clade B and 1clade AE (Thailand)trial did

not protect 13

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HIV Vaccine Development

Army, Thai Ministry of Health,NIAID, sanofi-pasteur

ALVAC (canary pox) carrying

HIV genes including anenvelope + AIDSVAX B/E

Low risk subjects14

ALVAC 120 92TH023 TM t t

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ALVAC gp120 92TH023-TM construct

lipid membrane

V3: green

cd4bs: yellow

V1V2: pink

17b-site: purple

gp120 N-terminus: dark blue

gp120 C-terminus: red

light blue: glycans

top view

core: 15 of 16 glycans built

v1v2: 6 of 8

v3: 1 of 1v4v5: included in core

TM domain

P. Huang, B. Schief

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HIV Vaccine Development

Army, Thai Ministry of Health,NIAID, sanofi-pasteur

ALVAC (canary pox) carrying

HIV genes including anenvelope + AIDSVAX B/E

Low risk subjects

31% protection 17

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Membrane proximal

Carbohydrate

CD4 binding site

V3 Loop

V1V2 Loops

V2,V3 Quaternary

(conformational)

CD4 binding site

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The RV144 ALVAC/HIV Prime, rgp120 B/E

Trial: Immune Correlates Analysis

Barton HaynesFor the RV144 Immune Correlates Working Group

September 13, 2011

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Objectives of the Study

RV144 Estimated Vaccine Efficacy = 31%(95% CI, 1.1 to 52.1, P=0.04)

Objective: To carry out a correlatesanalysis to begin to identify how thevaccine might work.

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Macrophage FcR-mediated

phagocytosis of virions and ADCC

of virus infected CD4 T cells.

NK cell FcR-mediated ADCC

5-9

CD4 T cells

Columnar EpitheliumStratified Squamous Epithelium

Mucus

Layer

2

4

Langerhan/dendritic cells CD4 T cells

HIV-1-infected cells

4

HIV-1 1

1

3

3

10,11

CD4

CCR5

47

HIV-1- CD4 interactions

NK Cell

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Definitions

Correlate of Risk-an immuneresponse that predicts whethervaccinees become HIV-1 infected.

It may be causally related toprotection from infection, or maybe only a surrogate marker foranother factor.

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Hypothesis Generating Study

Goal of the statistical analysis is todiscover correlates of risk

Such discoveries would generatehypotheses about the immuneresponses that contributed to

protection

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Case Control Study

Measured immune responses from:

41 Infected Vaccinees

205 Uninfected Vaccinees

40 Placebo Recipients

Question: What are the immunologicmeasurements in vaccinees that predict HIV-1

infection over 3 year follow-up? Sample Time point: 2 weeks (peak

immunogenicity) after final vaccination:

Cryopreserved specimens: 2.5 ml plasma and2 vials of cells 24

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HIV Vaccine Development--

Field is doing Two Things Figure out how ALVAC/HIV

AIDSVAX B/E worksthen make

it better

Figure out how to induce theantibodies against AchillesHeels of envelope that the body

doesnt normally want to make.25

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Membrane proximal

Carbohydrate

CD4 binding site

V3 Loop

V1V2 Loops

V2,V3 Quaternary

(conformational)

CD4 binding site